Preterm birth (PTB, born before 37 weeks of gestation) accounts for 12.5% of all births in the U.S. It is a leading cause of neonatal mortality and postnatal morbidity. The highest rate of PTB occurs among black population (17.8%). Available literature and our research strongly suggest that genetic factors play an important role in PTB. During the parent grant (R01HD41702) project period, our team has been investigating genetic (G) and environmental (E) determinants of PTB. Not only has our team made considerable progress in identifying susceptibility genes and GxE interactions in PTB, we have also established a large, multi-ethnic mother-infant cohort enrolled at Boston Medical Center (BMC). The goal of this competitive renewal application is to conduct a genome-wide association (GWA) study and apply advanced statistical methods to identify susceptibility loci of PTB. We will utilize the existent BMC cohort and address three primary aims: Aim 1A (Stage 1 GWA Study): We will conduct a GWA study among 1,000 black mothers who delivered preterm births (cases) and 1,000 age-matched black mothers who delivered term births (controls) at BMC. We will genotype all the 2,000 mothers using the Illumina HumanHap650Y BeadChip. We will test each SNP for association with PTB with adjustment for major covariates and population admixture. We will select SNPs that reach Stage 1 significance (p < 10-4) to be further tested in Stage 2 GWA. Aim 1B (Stage 2 GWA Study): We will genotype all the SNPs that reach Stage 1 significance identified from Aim 1A in an independent set of black mothers (500 cases and age-matched 1,000 controls) enrolled at BMC. We will perform confirmatory analysis of those SNPs reaching genome-wide significance (p < 2.05x10-7). We will also perform joint analysis (a total of 1,500 cases and 2,000 controls) of those SNPs that reach Stage 1, but not genome-wide significance. Aim 2 (Replication Study): We will further genotype the significant SNPs from Aim 1B in an independent set of White (~50%) and Hispanic (~50%) mothers enrolled at BMC: 500 preterm cases and 1,000 term controls matched by maternal ethnicity and age. We will perform replication analysis of the SNPs for White and Hispanic mothers, separately. Aim 3 (Effect of Fetal Gene): We will genotype the significant SNPs from Aim 1B in 1,500 preterm and 2,000 term babies born to the mothers to be genotyped in Aims 1A & 1B. We will examine if there is a main fetal gene effect on PTB and if the fetal gene interacts with the maternal gene to affect the risk of PTB. This will be the first large-scale GWA study of PTB in a multi-ethnic U.S population. We anticipate that this study will lead to identification of novel genetic loci of PTB. Such findings will not only provide important insights into mechanisms leading to PTB, but also may help identify women at high-risk of PTB, which in turn, may lead to development of early and targeted interventions that can prevent PTB or mitigate the severity and consequences of PTB. PUBLIC HEALTH REVELANCE: Preterm birth (PTB) accounts for 12.5% of all births in the U.S. It is a leading cause of neonatal mortality and postnatal morbidity. The goal of this study is to conduct a genome-wide association (GWA) study of PTB in a multi-ethnic U.S. population. We anticipate that this study will lead to identification of novel genetic loci of PTB, which may help develop a promising strategy to identify women at high-risk of PTB, and should have important implications for prevention and treatment of PTB.